All the publications mentioned throughout this application are fully incorporated herein by reference, including all the references cited therein.
The approach to the discovery of new anticancer drugs has recently evolved from cell-based screening to a more mechanistically based approach leading to many target-based drugs, for example with the development of protein kinase inhibitors. However, target-based screening assays may not be predictive of drug effect within the context of the whole cell, the cellular environment consisting of many additional influences on target function. On another hand, unexpected effects in cellular screening may suggest other targets or interactions. Also, the molecular understanding of cancer growth and metastasis is still developing, with the theory of the cancer stem cells (CSCs). In this context the development of new anticancer agents still represents a unique challenge with unpredictable outcome and a place for new and innovative compounds.
The inventors have generated and screened a new 2-arylquinoline compounds library against different human cancer cell lines (LNCaP, SkBr3, HepG2, HT29, B16F10, SK-MEL-28, U87-MG, BxPC-3, Capan-1, Capan-2, MIA PaCa-2, Panc-1, MOLM-14, U937, KG-1, Kasumi-1, HL60, NB4, SKM-1) and discovered novel anticancer agents, which in one case show an additional activity against human cancer stem cells (CSCs) which are widely incriminated in recurrence and relapse of cancer after therapy. An ALDH assay was used as cancer stem cell functional marker to describe the activity against CSCs (Greve, B. et al. Cytometry A 2012 (81) 284-293, Liu, S. et al. PLoS One 2013 (25) e81050, Ran, D. et al. Exp. Hematol. 2009 (37) 1423-1434, Cheung, A. M. et al. Leukemia 2007 (21) 1423-1430, Pearce, D. J. et al. Stem Cells 2005 (23) 752-760).
Therefore, it is an object of the present invention to provide active agents for preventing or inhibiting cell proliferation in a variety of organisms, and to provide methods for their synthesis.
It is another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of at least one active agent of the invention, alone or in combination with other active agents, and a pharmaceutically acceptable adjuvant, diluent or carrier.
It is another object of the present invention to provide active agents for use in therapy.
It is another object of the present invention to provide a method for the treatment and/or prevention of a proliferative and/or neoplastic disease.
It is another object of the present invention to provide a method for inhibiting the growth or differentiation of a Cancer Stem Cell (CSC), a tumor initiating cell, a mesenchymal-like cell associated with cancer, a mesenchymal cancerous cell, or a mesenchymal cell.
The above and other objects and advantages of the invention will become apparent as the description proceeds.